Three-dimensional artificial callus distraction

ABSTRACT

The present invention relates to devices for the regeneration of bone by three-dimensional callus distraction. The invention further relates to the use of such devices and to methods for three-dimensional callus distraction.

The present invention relates to a device for the regeneration of abone, in particular by means of three-dimensional distraction, a methodfor three-dimensional callus distraction, and uses of said device.

At the present time, bone losses are generally filled using bonereplacement materials, or autogenic or allogenic bone.

Examples of bone replacement materials include inorganic materials suchas calcium phosphate, hydroxyapatite, or bioglass (which should bereplaced by bone after a long absorption period. However, this proceduremay be used only for minor defects; otherwise, there is the risk ofinfection due to insufficient vascularization. The absorption ofinorganic materials is inadequate. Such bone materials, i.e., bonereplacement materials, do not emit biomechanical pulses and therefore donot initiate active regeneration) and include also syntheticallymanufactured organic materials, such as polyesters, polyamino acids,polyanhydrides, polyorthoesters, polyphosphazenes, polylactides, orpolyglycolides, or allogenic organic materials, for example of bovineorigin. Material combinations of the various types of materials are alsoused as bone replacement composites. However, bone substance losses mayalso be compensated for using microvascular connected autogenic orallogenenically vascularized transplants. However, use of an allogenicbone replacement may trigger undesired immune reactions and transmitinfection.

From a biological standpoint, the best replacement material for bone isan autologous spongiosa transplant. However, such transplants havelimited availability and exhibit a high absorption rate aftertransplantation.

The materials and techniques used in the prior art frequently provideunsatisfactory bone quality, resulting, for example, in insecureanchoring of implant beds. In addition, frequently the bone replacementis insufficiently vascularized, thereby increasing the risk ofinfection. Furthermore, methods of the prior art often use growthfactors which greatly increase the costs for the methods.

Instead of using a bone replacement, missing bone substance maysometimes be filled by bone regeneration. Segmented interruptions in theosseous continuity of long tubular bones may be treated in this mannerby distraction osteogenesis.

Callus distraction has been known for over a hundred years. The mostimportant biological stimulus for bone formation is mechanical stress.This releases piezoelectric forces which activate the osteoblasts andosteoclasts. Distraction osteogenesis induces new bone formation bytriggering biological growth stimulation by means of slow separation ofbone segments. This method achieves direction formation of woven bone bydistraction. The defined tensile stress is essential for bone formation.When such a defined tensile stress is applied to bone fragments, themesenchymal tissue exhibits an osteogenetic potential in the gap and atthe contiguous fragment ends. When sufficient vascular potency ispresent, progressive distraction results in metaplasia of the organizedhematoma, also referred to as blood coagulum, in a zone oflongitudinally arranged fibrous tissue, which under optimal external andinternal conditions may be directly converted to woven bone. Acomplication, however, is that the bone tissue requires highly complexcontrol for regeneration.

WO 01/91663 describes a two-dimensionally oriented bone distractionusing an artificial interface. For such distraction methods from theprior art, in many cases only vertical regeneration is possible, forexample in the jaw region.

Thus, bone regeneration by distraction cannot be used for every type ofbone defect. In addition, the devices used for distraction are complex,and distraction methods take a comparatively long time.

The technical object of the present invention is to provide a devicewhich allows bone regeneration methods to be carried out which overcomethe disadvantages of the prior art. A further technical object of theinvention is to provide devices, use of same, and methods which allowsimple and economical bone regeneration. A further technical object ofthe invention is the provision of devices, use of same, and methodswhich have improved quality and sufficient vascularization.

The technical object is achieved by the present invention in particularby providing devices, methods, and uses according to the claims.

The technical object is achieved by the present invention in particularby providing a three-dimensional framework for regenerating bone,comprising framework fibers composed of at least one framework materialand interspaces enclosed by same, wherein the framework material isbiocompatible, and expandable and/or shrinkable in a predefined andcontrolled manner as a function of an internal or external force effect,and the starting volume of the framework may be changed in a predefinedand controlled manner as a function of the internal or external forceeffect.

Provision of the described three-dimensional framework allows theframework to be introduced into a bone defect, for example by surgicalmeans. After introduction into the bone defect, according to theinvention the volume of the introduced three-dimensional frameworkchanges, for example increases or decreases in size, as the result ofits design and composition, either directly and automatically withoutfurther action, or after introduction of an internal or external force.As a result, after introduction of the framework into the bone defect,osteogenic cells or cell aggregates which have migrated into the bonedefect and adhered to the framework fibers are slowly exposed in adefined manner to stress, i.e., biomechanical stimulus, in particularwhen they are located at a distance from the framework for whichdistraction is effective, so that a callus precursor is produced in theentire defect all at once by distraction, and then only needs to ossify.This stimulus is advantageously achieved in essentially all cells at thesame time. According to the invention, biomechanical stimuli may betransmitted directly to the osteoblasts without the need forfibroblasts. Thus, the distraction may act on the osteoblasts withcomparatively small forces.

The framework according to the invention may advantageously be used inmethods, preferably methods according to the invention, for boneregeneration, in particular for three-dimensional callus distraction.

The present teaching encompasses in particular devices and methods forbone regeneration, wherein preferably bone in the jaw region and/orperiodontal region is to be regenerated.

In particular, for the present invention the term “bone regeneration” isalso understood to mean the regeneration of bone defects, for exampleafter cystectomy, tumor surgery, or trauma surgery, etc., regardless ofthe topography, and/or in particular also means the regeneration ofminor bone defects, for example those caused by periodontitis.

In the context of the present invention, a “framework” is understood tomean a three-dimensional body. The framework comprises framework fiberscomposed of a framework material, as well as interspaces between theframework fibers. The framework fibers define the shape, border, andsize of the framework, and are designed and configured in such a waythat they result in a three-dimensional body (the framework) whichdefines a specified volume and which contains interspaces, for examplepores, cavities, gaps, or hollow spaces, between the framework fibers.The volume of the framework may be changed, for example in a plastic orelastic manner, by a force effect, preferably without altering thestructural identify of the framework, for example without removing oradding to the framework material. Such a framework may be present, forexample, in the form of an interwoven mesh, porous cushion, sponge-likebody, or matrix.

In the context of the present invention, “interspaces” of athree-dimensional framework according to the invention are understood tomean the volume of the framework which is not filled by a solidmaterial, in particular by the framework fibers, and which is situatedinside the overall volume of the framework. The interspaces may havevarious volumes, which, however, as a whole are smaller than the overallvolume of the framework. The interspaces may have any shape. Accordingto the invention the interspaces are preferably pores. The interspaces,for example pores, preferably have a diameter of 10 μm to 10 mm,preferably 10 μm to 1000 μm.

According to the invention the framework preferably containsinterspaces, for example pores, having a maximum diameter of 100 μm.According to the invention, the framework preferably containsinterspaces having a diameter of greater than 450 μm. According to theinvention, the framework preferably contains interspaces having adiameter less than 100 μm as well as interspaces having a diametergreater than 450 μm. The framework material from which the framework isformed may use cells as a support structure. Pores having a pore size ofless than 100 μm, for example, enable the growth of connective tissue.For pores with a pore size greater than 450 μm, blood vessels are ableto grow into the framework and thereby vascularize the volume occupiedby the framework.

According to the invention, at least a portion of the interspaces,particularly preferably the pores, preferably have a diameter of 0.5 μmto 5 μm. According to the invention, at least a portion of theinterspaces, particularly preferably the pores, preferably have adiameter of 5 μm to 25 μm. According to the invention, at least aportion of the interspaces, particularly preferably the pores,preferably have a diameter of 100 μm to 1000 μm. According to theinvention, at least a portion of the interspaces preferably have adiameter of 0.5 μm to 5 μm, a portion of the interspaces have a diameterof 5 μm to 25 μm, and a portion of the interspaces have a diameter of100 μm to 1000 μm. According to the invention, preferably one-fourth,particularly preferably one-third, most particularly preferablyone-half, of the interspaces, particularly preferably the pores, have adiameter of 0.5 μm to 5 μm. According to the invention, preferablyone-fourth, particularly preferably one-third, most particularlypreferably one-half, of the interspaces, particularly preferably thepores, have a diameter of 5 μm to 25 μm. According to the invention,preferably one-fourth, particularly one-third, most particularlypreferably one-half, of the interspaces, particularly preferably thepores, have a diameter of 100 μm to 1000 μm.

According to the invention, the diameter of the interspaces ispreferably at least 450 μm and 5 mm maximum, particularly preferably atleast 450 μm and 1000 μm maximum.

According to the invention, the framework preferably has open-pore guidestructures which have a porosity that is particularly preferably 50% to70%, in particular 60%, and which enable ingrowth of blood vessels.

According to the invention, the interspaces, for example pores, have asize, in particular a diameter, which allows transmission of extensionstimuli to the cells present in the pores, of at least 0.5 μm, inparticular 1 μm, more preferably 2 μm, most preferably 10 μm toespecially 100 μm, particularly preferably 1000 μm, more particularlypreferably 1 cm, most particularly preferably up to 10 cm. According tothe invention, the extension stimuli are preferably transmitted with adistraction frequency of 1 mm/day maximum.

In the context of the present invention, the “volume” of athree-dimensional framework according to the invention is understood tomean the volume that is delimited by the framework fibers which definethe outer surfaces of the framework. Thus, the volume of the frameworkis formed by the volume of the framework fibers and the volume of theinterspaces enclosed by the framework fibers. The three-dimensionalframework according to the invention is preferably present in the formof a starting volume, preferably the original volume, which is able tochange to a different volume as the result of an internal or externalforce effect. A change in the volume means a change in the startingvolume, specifically, either an increase in the starting volume, forexample by expansion of the framework, or a decrease in the startingvolume, for example by compression or shrinkage of the framework.

According to the invention, the framework material is expandable and/orshrinkable in a predefined and controlled manner as a function of aninternal or preferably external force effect. The material may haveplastic or elastic properties. These properties of the frameworkmaterial allow the capacity of the framework provided according to theinvention to reversibly or irreversibly change in a predefined andcontrolled manner.

In the context of the present invention, “in a predefined and controlledmanner” is understood to mean a change in the starting volume, inparticular an expansion or shrinkage, which occurs over a predetermineddistance or a predetermined volume, and whose rate, i.e., the expansionrate, shrinkage rate, or rate of change in volume, is likewisepredetermined, i.e., intentionally selected. According to the invention,a change in the volume may also be only a change in the shape of thevolume. According to the invention, the point in time of the expansion,shrinkage, or start of the change in volume may also preferably bepredetermined, i.e., intentionally selected.

According to the invention, the starting volume of the three-dimensionalframework may preferably be changed by an externally supplied force.According to the invention, the force is preferably supplied using atension cable or tension rod. According to the invention, the suppliedforce is preferably heat. According to the invention, the supplied forceis preferably ultrasound. According to the invention, the force ispreferably supplied by a magnet, and is therefore an electromagneticforce. According to the invention, the force may also preferably be apressure exerted by, for example, a liquid or gas supplied from outsidethe framework.

According to the invention, the starting volume of the framework maypreferably be changed by diffusion of a liquid, in particularinterstitial liquid, into the framework system as the result ofcolloidal osmotic pressure. According to the invention, a necessaryconcentration gradient is preferably achieved by using dextran and/orhydroxylethyl starch.

In the context of the present invention, “expansion” is understood tomean an enlargement of the framework along at least one spatial axis,preferably along all three spatial axes. According to the invention, anexpansion preferably results in an increase in volume of the framework.

In the context of the present invention, “shrinkage” is understood tomean a reduction in size of the framework along at least one spatialaxis, preferably along all three spatial axes. According to theinvention, the shrinkage of a framework preferably causes a reduction inthe volume of the framework.

According to the invention, the shrinkage is preferably compression.Thus, according to the invention the framework material is compressiblein a predefined and controlled manner as a function of an internal, orpreferably external, force effect, so that in this manner the volume ofthe framework may also be changed. In the context of the presentinvention, “compression” is understood to mean shrinkage in which theframework is pressed together by an external force effect.

According to the invention, the starting volume may preferably beincreased by filling the interspaces of the framework, particularlypreferably the pores of the framework, with a liquid, particularlypreferably a liquid containing biomolecules and/or cells, mostpreferably blood, preferably by a pressure exerted inwardly on theframework fibers by the inflowing liquid.

In the context of the present invention, “filling the interspaces” isunderstood to mean an at least partial inflow of a liquid into theinterspaces. According to the invention, in the filling the interspacesare preferably filled for the most part, most preferably completely,with the liquid.

According to the invention, the framework preferably has at least one,preferably biodegradable, molded element. According to the invention themolded element is preferably a casing. According to the invention themolded element is preferably an interlacing, for example a thread.According to the invention the molded element is preferably an adhesive.

According to the invention the framework is preferably a molded element,as the result of which the framework is in an expanded starting volume.According to the invention the framework preferably has at least onemolded element, as the result of which the framework is in a compressedstarting volume. According to the invention the framework is preferablya molded element, as the result of which the framework is in an expandedor compressed starting volume, wherein the starting volume may bechanged by removing the molded element, preferably mandatorily andautomatically, in particular wherein the framework is present in anonexpanded or uncompressed state.

According to the invention, the material of the molded element ispreferably selected from the group comprising fibrin, collagen, at leastone polysaccharide, and mixtures thereof. According to the invention,the biodegradable molded element is preferably fibrin or contains same.According to the invention, the biodegradable molded element ispreferably collagen or contains same. According to the invention, thebiodegradable molded element is preferably at least one polysaccharideor contains same.

According to the invention, the starting volume of the framework ispreferably compressed or shrunk. According to the invention, thestarting volume of the framework is preferably extended or expanded.According to the invention, the framework is kept in the particularshape in a compressed or expanded state by a biodegradable moldedelement.

According to the invention, the framework is preferably initiallymechanically compressed or expanded after manufacture. According to theinvention, the framework is preferably compressed by pressure or bydrying and shrinkage. In one preferred design, the framework is thenprovided with the molded element in order to maintain the compressed orexpanded starting volume until the start of the desired distraction.

According to the invention, the three-dimensional framework preferablyhas an elastic restoring force. Before the framework is used, thestarting volume of the framework is changed, in particular compressed.In this state fixing is performed using a biodegradable molded element,for example an adhesive. When this biodegradable molded element, forexample the adhesive, decomposes, the volume of the framework is changedby the elastic restoring force, thus allowing biomechanical stimuli tobe triggered.

According to the invention, the three-dimensional framework preferablycontains a spring made of biodegradable material. According to theinvention, the spring, preferably in the compressed or stretched state,is fixed using a biodegradable molded element, for example a thread oradhesive. When the molded element disintegrates as the result ofdecomposition, i.e., absorption, the spring integrated into theframework causes the framework to change shape and thus emitbiomechanical stimuli.

According to the invention, the absorption time for the molded elementis shorter, in particular much shorter, than the absorption time for theframework.

According to the invention, the absorption time for the molded elementis preferably at least one day, particularly preferably at least fivedays, most preferably at least seven days. According to the invention,the absorption time for the molded element is preferably twenty daysmaximum, more preferably fifteen days maximum, most preferably five daysmaximum.

According to the invention, the degradation kinetics of the frameworkand of the framework material are adapted to the time schedule of avolume distraction to be carried out using the framework according tothe invention.

According to the invention, the starting volume of the three-dimensionalframework is preferably changed at a predetermined rate. According tothe invention, the maximum rate at which the starting volume of theframework is able to change is preferably great enough so that the cellsadhering to the framework are distracted a maximum of 1.5 mm/day,particularly preferably 1.2 mm/day, in particular 1 mm/day, mostpreferably 0.9 mm/day.

In one preferred embodiment, the volume may be changed in a predefinedand controlled manner at a rate at which expansion or shrinkage of avolume of 1000 μm³ to 216,000 μm³ in all three spatial coordinates is amaximum of 0.6 mm per day, particularly preferably a maximum of 0.577 mmper day, in particular a maximum of 0.55 mm per day, most preferably amaximum of 0.5 mm per day. In one preferred embodiment, the volume maybe changed in a predefined and controlled manner at a rate at whichexpansion or shrinkage of a volume of 1000 μm³ to 216,000 μm³ in allthree spatial coordinates is a minimum of 0.01 mm per day, particularlypreferably a minimum of 0.1 mm per day, in particular a minimum of 0.2mm per day, most preferably a minimum of 0.5 mm per day.

In one preferred embodiment, the volume may be changed in a predefinedand controlled manner at a rate at which expansion or shrinkage of asection, between 10 μm and 60 μm long, of the body diagonal of thevolume of the framework is a maximum of 0.6 mm per day, particularlypreferably a maximum of 0.577 mm per day, in particular a maximum of0.55 mm per day, most preferably a maximum of 0.5 mm per day. In onepreferred embodiment, the volume may be changed in a predefined andcontrolled manner at a rate at which expansion or shrinkage of asection, between 10 μm and 60 μm long, of the body diagonal of thevolume of the framework is a minimum of 0.01 mm per day, particularlypreferably a minimum of 0.1 mm per day, in particular a minimum of 0.2mm per day, most preferably a minimum of 0.5 mm per day.

According to the invention, the framework is preferably designed in sucha way that the starting volume may be changed continuously. According tothe invention, the framework is preferably designed in such a way thatthe changes in the starting volume may occur discontinuously.

According to the invention, the framework material, preferably theframework fibers, are not biogenic, and in particular contain nocollagen, i.e., are collagen-free. According to the invention theframework material is preferably biogenic.

According to the invention the framework material is biocompatible.

According to the invention, the framework material preferably has atleast one cell adhesive property, i.e., is able to bind cells, inparticular osteoblasts, fibroblasts, and/or endothelial cells,preferably in a specific and selective manner. According to theinvention, the cell adhesive property of the framework material ispreferably determined by its surface characteristics.

According to the invention, the framework material and/or the frameworkare preferably biodegradable.

In the context of the present invention, “biodegradable” is understoodto mean that the material may be degraded or absorbed by hydrolysis,polymer degradation, enzymatic decomposition, and/or dissociation of thematerial components, preferably in an organism, for example a human oranimal organism. According to the invention, the degradation products ofthe framework material preferably have a molecular weight of 50,000g/mol maximum, particularly preferably 40,000 g/mol maximum. Thus, theymay be excreted in the normal manner.

According to the invention, the biodegradable framework material ispreferably degraded in an organism within an absorption time of oneyear, particularly preferably within two months, in particular withinone month, most preferably within two weeks.

According to the invention, the absorption preferably begins 6 weeksafter the framework is introduced into an organism.

According to the invention, the absorption time for the frameworkmaterial and/or the framework is particularly preferably at least 4weeks, particularly preferably at least 8 weeks, in particular at least16 weeks, most preferably at least 32 weeks. According to the invention,the absorption time for the framework material or the framework ispreferably a maximum of 52 weeks, particularly preferably a maximum of38 weeks, more preferably a maximum of 16 weeks, most preferably amaximum of 8 weeks.

According to the invention, the framework material is preferablycomposed of at least one polymer or contains same, and is preferablycomposed of spatially crosslinked polymers. Influx of water, blood, orserum results in formation of, for example, hydrogen bridges, sulfurbridges, or the like which cause spatial changes in the polymericstructure, resulting in a three-dimensional motion which generates apulse for biomechanical stimulus transmission to the embedded cells.

According to the invention, the framework material preferably has goodprocessing characteristics. According to the invention, the frameworkmaterial and/or framework are sterilizable. According to the invention,the framework may preferably be adapted satisfactorily to theregeneration geometry. According to the invention, the frameworkmaterial and/or framework preferably have good storage characteristics.

According to the invention, the framework material preferably contains amaterial selected from the group comprising polyglycolic acid,polylactic acid, poly(ε-caprolactone), poly(β-hydroxybutyrate),poly(p-dioxanone), a polyanhydride, or a mixture thereof, for example amixture of polylactic acid and polyglycolic acid.

According to the invention, the framework material preferably containscopolymers, in particular composed of at least two of the previouslynamed materials. According to the invention, the framework materialpreferably contains polymer mixtures.

According to the invention, the framework material is preferablycomposed of a material selected from the group comprising polyglycolicacid, polylactic acid, poly(ε-caprolactone), poly(β-hydroxybutyrate),poly(p-dioxanone), a polyanhydride, or a mixture thereof. According tothe invention, the framework material preferably contains copolymerscomposed of at least two of the previously named materials.

According to the invention, the framework material is preferablycomposed of polylactic acid and polyglycolic acid. According to theinvention, the polylactic acid and polyglycolic acid are preferablypresent as a copolymer.

According to the invention the framework material is preferablypolyglycolic acid or contains same. According to the invention theframework material is preferably polylactic acid or contains same.According to the invention the framework material is preferablypoly(ε-caprolactone) or contains same. According to the invention, theframework material is preferably poly(β-hydroxybutyrate) or containssame. According to the invention the framework material is preferablypoly(p-dioxanone) or contains same. According to the invention theframework material is preferably at least one polyanhydride or containssame. According to the invention other suitable materials may alsopreferably be used.

According to the invention, the framework material is preferablycomposed of at least one polylactite and at least one polyglycolide.

According to the invention, copolymers having different physical andmechanical properties may preferably be produced by the combination andvariation of the lactite and glycolide fractions and used as frameworkmaterial.

According to the invention, the framework material preferably hasspecific rubber-elastic properties and has sufficient mechanicalstability to overcome the tissue pressure present in the defect regionof the bone. In particular, in one preferred embodiment the frameworkmaterial and/or framework are capable of resisting an effective tissuepressure of up to 9.5 mm Hg in the tissue surrounding same.

According to the invention, the framework material is preferablyanisotropic. In the context of the present invention, “anisotropy” isunderstood to mean the spatial variation in the macroscopic mechanicalproperties.

According to the invention, the surface of the framework material ispreferably enlarged, in particular by providing contours. Thisenlargement not only increases the surface that is available to thecells, but also influences the organization of the cell growth.

According to the invention, the size and spatial distribution of theinterspaces, in particular the pores, in the framework preferablydetermine the availability of the interspaces or pores to cells andexchange of nutrients. With increasing metabolic activity of the cells,the thickness of the blood vessels also increases in order to keep themetabolic paths by diffusion and osmosis between the active cells andthe blood at a minimum. According to the invention, it is preferred toachieve the metabolism by providing suitable vascularized macroporosity.In a fine-pored framework the metabolism must overcome large distances,so that diffusion becomes the limiting factor.

According to the invention, the framework fibers preferably have athickness of 5 to 3000 μm, preferably 50 μm to 3000 μm, preferably 60 μmto 2000 μm, in particular 100 μm to 1000 μm. According to the invention,the framework material, in particular the framework fibers, have adiameter of 5-50 μm.

According to the invention, the framework material, in particular theframework fibers, preferably have a thickness of 1-5 g/cm³. According tothe invention, the framework material, in particular the frameworkfibers, preferably have rigidity and ductility, and a strength of1000-8000 MPa. According to the invention the framework material, inparticular the framework fibers, preferably have a modulus of elasticityof 50-500 GPa. According to the invention, the framework material, inparticular the framework fibers, preferably have an elongation at breakof 0.2-10%.

According to the invention, the framework preferably contains cells inthe interspaces, in particular endothelial cells and/or osteoblastsand/or fibroblasts, before the introduction into a defect region of abone.

According to the invention, the framework material is preferablycomposed of at least one fiber composite or contains same. According tothe invention, the framework material is preferably composed of fibersof a fiber composite or contains same. According to the invention, theframework material is optionally encased by a thermoplastic matrix or isembedded in same. According to the invention, mechanical protection ofthe fibers under pressure and shear stress, strength under strain, andprotection of the recipient tissue from the integrated fiber particlesare thus provided. In particular, the invention optionally providessealing of the three-dimensional fiber structure surface. The fibers maypreferably be embedded in a matrix having, for example, a differentlayer thickness. According to the invention, in the framework materialfibers of a fiber composite are preferably partly or completely embeddedin a polymer matrix.

According to the invention the framework material is preferably coated.According to the invention the framework material is preferably coatedusing thin-layer technology. According to the invention the frameworkmaterial is preferably coated using vacuum, plasma, or ion technology.Desired protein adsorption may be influenced in a targeted manner usinga coating preferred according to the invention. In addition,hemocompatibility may be improved by coating with antithrombogenicsurfaces. Cell adhesion to the framework material and influencing ofcell growth of the adhered cells may be achieved in a controlled mannerusing a thin coating preferred according to the invention. Theelectrical properties of the surface of the framework material may bemodified in a targeted manner using a coating preferred according to theinvention.

According to the invention, the fibers of a fiber composite maypreferably be coated to increase the cell adhesion. According to theinvention the fibers are preferably coated with titanium. According tothe invention the framework material is preferably coated with titanium.According to the invention the fibers are preferably coated withtitanium oxide. According to the invention the framework material ispreferably coated with titanium oxide. According to the invention thefibers are preferably coated with sodium alginate. According to theinvention the framework material is preferably coated with sodiumalginate.

According to the invention the fibers are preferably coated with ahydrogel. According to the invention the framework material ispreferably coated with a hydrogel. According to the invention, thehydrogel coating may preferably be used so that the volume of theframework does not immediately change after the framework is introducedinto a bone defect, or does not change until a later point in time,particularly preferably after one week.

To allow the most effective use possible of the framework according tothe invention, osteoblasts must be able to bind well to the frameworkfibers. As the result of improved adhesion between the framework and theosteoblasts, when a framework according to the invention is used, inparticular in a method according to the invention, more osteoblasts areactivated by the framework by means of one or more biomechanical pulses.For this reason, the framework material or the coating for the frameworkmaterial is preferably designed according to the invention in such a waythat optimum osteoblast binding to the framework can take place.According to the invention, the adhesion binding of the osteoblasts tothe framework is preferably so strong that the binding is maintainedduring a portion of the volumetric expansion, particularly preferablyduring the entire volumetric expansion, of the framework, in particularwhen the framework is used in a method according to the invention.

According to the invention the fibers are preferably smooth. Accordingto the invention the framework material is preferably smooth. Accordingto the invention the coating for the framework material is preferablysmooth. According to the invention the fibers are preferably rough.According to the invention the framework material is preferably rough.According to the invention the coating for the framework material ispreferably rough. A large surface is available for binding of theosteoblasts by use of a preferred rough surface according to theinvention.

According to the invention the fibers are preferably coated withhydroxyapatite. According to the invention the framework material ispreferably coated with hydroxyapatite. A coating with hydroxyapatitepreferred according to the invention allows binding-promoting adsorptionof proteins.

According to the invention the fibers are preferably coated with ahydrogel. According to the invention the framework material ispreferably coated with a hydrogel. According to the invention thehydrogel layer is thin.

According to the invention the fibers are preferably coated with atleast one protein. According to the invention the framework material ispreferably coated with at least one protein. According to the inventionthe at least one protein contains the amino acid sequence Arg-Gly-Asp,i.e., RGD. According to the invention the fibers are preferably coatedwith at least one peptide. According to the invention the frameworkmaterial is preferably coated with at least one peptide. According tothe invention the at least one peptide is preferably a peptide whichinitiates the cell adhesion. According to the invention the at least onepeptide is preferably an RGD peptide. According to the invention the atleast one peptide is preferably synthetically produced. According to theinvention the at least one peptide preferably contains the amino acidsequence Arg-Gly-Asp, i.e., RGD. According to the invention the at leastone peptide preferably comprises the amino acid sequence Arg-Gly-Asp,i.e., RGD.

According to the invention the fibers are preferably coated withstar-shaped polyethylene glycol polymers (star PEG). According to theinvention the framework material is preferably coated with star-shapedpolyethylene glycol polymers (star PEG).

According to the invention, the at least one protein is preferably boundto the polyethylene glycol polymer coating, particularly preferablycovalently bound. According to the invention, the at least one peptideis preferably bound to the polyethylene glycol polymer coating,particularly preferably covalently bound.

The adhesion of osteoblasts is a receptor-mediated contact between themolecules of the extracellular matrix and the actin fibers of thecytoskeleton. This region is also referred to as the focal contact zone.Molecules which provide for binding as well as molecules which areresponsible for signal transduction are present in the focal contacts.Formation of the focal adhesion is caused primarily by integrins. Theintegrins differ from other cell surface receptors by virtue of theirbioaffinity. Adhesion proteins in the form of an ultrathin coating onthe framework material facilitate the adhesion binding of osteoblasts tothe framework according to the invention. Fibronectin is anextracellular adhesion protein having several specific binding sites forreceptors, and is therefore used for binding the osteoblasts to theextracellular matrix. Fibronectin is a large glycoprotein, which as adimer is composed of two essentially identical subunits. Fibronectin iscomposed of approximately 90 amino acids. The cell-binding site offibronectin has been identified as the tripeptide sequence Arg-Gly-Asp(RGD).

The properties of the fiber composites, with or without a matrix, maypreferably be specified according to the invention by the fibervolumetric capacity and by the orientation of the fibers in the fiberarchitecture. In this manner the strength and the modulus of elasticityof the framework according to the invention may also preferably bespecified according to the invention.

If the framework is preferably according to the invention composed offibers of a fiber composite, or if the framework contains such fibers,the framework according to the invention is preferably designed in sucha way that a stress is able to occur in the fiber direction orperpendicular to the fiber direction. However, according to theinvention the framework may also be designed in such a way that stressesare able to occur in various directions in relation to the fiberdirection. According to the invention, for a stress perpendicular to thefiber direction the fibers are preferably arranged in series. When amatrix is preferably used between the fibers according to the invention,this matrix is thereby subjected to greater stress.

According to the invention, the three-dimensional framework is composedof a fiber composite made of continuous fibers, or contains same.

According to the invention, a framework is preferably composed of afiber composite made of differently oriented layers. According to theinvention, the layer sequence of the fibers may preferably besymmetrical to the center plane of the framework, or may be configuredrandomly or in intermediate stages.

According to the invention, fibers of a fiber composite preferablyrepresent the primary load-bearing element of a framework having athermoplastic matrix. Because of their higher modulus of elasticity andhigher strength, the fibers largely determine the mechanical propertiesof the composite.

According to the invention, the framework preferably contains a fiberarchitecture in the form of a nonwoven fabric, a two-dimensionalframework, a multiaxial framework, and/or a three-dimensional interwovenmesh.

According to the invention, a unidirectional woven fabric is preferablyused as the fiber architecture for the framework.

According to the invention, the fiber architecture of the framework ispreferably a biaxial woven fabric. According to the invention, the fiberarchitecture of the framework is preferably a knitted fabric. Accordingto the invention, the fiber architecture of the framework is preferablya multiaxial, multilayered knitted fabric.

According to the invention, the framework is preferably characterized byits biofunctionality. The physical, mechanical, and/or biologicalproperties in conjunction with the time-related biomechanical stimulusemission are important for biofunctionality.

The selection of specific preferred architectures according to theinvention, in particular knitting techniques, for the design of theframework composed of the framework material allows the density,distribution, and orientation of the framework material to becontrolled, and is an effective means for designing structures whichprovide controllability of the mechanical behavior and the growth ofcells into the framework.

According to the invention, the surface of the framework material ispreferably chemically modified. According to the invention, the surfaceof the framework material is preferably chemically modified by reactivemolecules or groups of molecules. According to the invention, themolecules or groups of molecules by means of which the surface of theframework material is chemically modified are preferably able to reactwith anchor proteins of the extracellular matrix of cells. According tothe invention the surface of the framework material is preferablyhydrophilic. Hydrophilic surfaces allow better adhesion for cells thando hydrophobic surfaces. The surfaces of each framework correspond tothe polarizability of the framework.

The invention further relates to a three-dimensional framework which fora specified period of time is able to pulse or vibrate, for example asthe result of excitation by a magnetic field or ultrasound, thusallowing emission of biomechanical stimulus pulses for osteogenic cells.

According to the invention, the structural elements of the framework maypreferably be configured according to a stochastic, fractal, or periodicprinciple.

According to the invention the framework is preferably composed ofsubstructures and simple subsystems. According to the invention, thecomplexity of the framework may preferably be increased by ahierarchical sequence of structural elements over several stages inwhich the smallest functioning unit is combined into groups, which inturn are combined with additional groups having a differentfunctionality to produce larger units.

According to the invention, a plurality of frameworks may preferablyalso be present in the form of a granulate. The base units of thegranulate, i.e., the individual frameworks, have an identical or similardesign, but are not combined into a superstructure. According to theinvention the individual granule particles, i.e., the individualframeworks, are preferably fixed to one another using a biodegradableadhesive, and in this manner may be incorporated into the defect.

The invention further relates to the use of at least onethree-dimensional framework according to the invention described withinthe scope of the present teaching, in one preferred embodimentoptionally containing a spring, for producing a bone regeneration kit.The invention further relates to the use of a granulate according to theinvention, composed of frameworks for producing a bone regeneration kit.According to the invention, said kits preferably contain at least onesurgical instrument, particularly preferably at least one applicator,for example a syringe, and a capsule for accommodating the framework,for example the framework in granulate form. According to the invention,the kit preferably contains a user's manual. According to the invention,the kit preferably contains packaging, particularly preferably packagingwhich allows sterile storage of the framework. According to theinvention, the kit preferably contains an adhesive, in particular anadhesive for fixing the framework in a bone defect.

In a further embodiment of the invention, the invention relates to theuse of a three-dimensional framework according to the invention forproducing a bone regeneration kit, the kit also having a molded elementof the above-referenced type, for example a casing, an adhesive, or aninterlacing.

The invention further relates to the use of a biocompatible frameworkmaterial which is expandable and/or shrinkable in a predefined andcontrolled manner as a function of an internal or external force effect,and which has a cell adhesive property for producing a three-dimensionalframework comprising a framework material and interspaces enclosed bysame for regeneration of a bone, wherein the three-dimensional frameworkmay be introduced into a defect region of a bone.

The invention further relates to provision of a method for producing athree-dimensional framework for regeneration of a bone, wherein, using abiocompatible framework material which is expandable and/or shrinkablein a predefined and controlled manner as a function of an internal orexternal force effect, and which has a cell adhesive property, aframework is formed which is able to change its starting volume in apredefined and controlled manner as a function of the internal orexternal force effect.

The invention relates in particular to a method for producing athree-dimensional framework according to the invention, whereinframework fibers composed of at least one nonbiogenic framework materialare formed into a framework in an extrusion process, the frameworkmaterial being biocompatible, and being expandable and/or shrinkable ina predefined and controlled manner as a function of a force effect, andhaving a cell adhesive property.

According to the invention, the interspaces which are enclosed by theframework material are produced by leaching out salts from salt-polymermixtures.

According to the invention, for production of the framework fibers feltsmade of polymer fibers may preferably be stabilized by gluing the fibersin the framework. According to the invention the framework material, inparticular a polymer, may be foamed using thermally activated foamingagents or by pressurized expansion. According to the invention, theinterspaces which are enclosed by the framework material are preferablyproduced using a sol-gel process.

The invention achieves its underlying technical object, and thereforefurther relates to provision of a method for regeneration of a bone,wherein at least one above-referenced three-dimensional framework, inparticular comprising a framework material forming framework fibers andinterspaces enclosed by the framework fibers, is introduced into adefect region of a bone, wherein the framework material isbiocompatible, and is expandable and/or shrinkable in a predefined andcontrolled manner as a function of a force effect, and has a celladhesive property, in particular for osteoblasts, fibroblasts, and/orendothelial cells, and wherein the framework is subjected to an internalor external force effect, and the starting volume of the frameworkchanges in a predefined and controlled manner as a function of the forceeffect.

Accordingly, within the scope of the method according to the inventionfor bone regeneration, in one preferred embodiment a three-dimensionalframework is introduced into a defect region of a bone. In this defectregion the framework is enclosed by a blood clot; i.e., the surfaces ofthe framework in the framework interior as well as on the externalsurfaces make contact with the autologous cells contained in the bloodclot. According to the invention the interspaces enclosed by theframework material are preferably filled at least partially,particularly preferably for the most part, in particular completely, bythe blood clot. Since the framework has a three-dimensional design, theframework surface comes into contact with the autologous cells containedin the blood clot in the entire space that is filled by the framework.After the framework has been introduced into the defect region of abone, a change in volume, i.e., in particular a decrease or increase involume, of the framework is triggered, for example by the action of anexternal or internal force, for example also by removing a moldedelement. This results in the desired biomechanical stimulation of theembedded osteogenic cells, and thus results in distraction and thereforebone regeneration. According to the invention, the force effectpreferably occurs within the body, in particular within the bone defect.According to the invention, the force effect preferably occurs on amolded element, for example an adhesive or a thread, which fixes thethree-dimensional framework in a compressed and/or expanded state.According to the invention, the molded element, for example theadhesives or threads, is preferably destroyed, in particularbiodegraded, by an external force effect. As the result of destructionof the molded element, for example the adhesive or thread, thethree-dimensional framework is able to return to the unexpanded and/oruncompressed state, thereby changing the volume of the three-dimensionalframework.

According to the invention, the volume of the framework is changed as afunction of an external force effect. According to the invention, theexternal force effect preferably occurs outside the body. According tothe invention, the external force effect preferably occurs via tensioncables and/or rods. According to the invention, the external forceeffect preferably occurs by means of at least one magnet. According tothe invention, the force effect preferably occurs by means ofultrasound.

According to the invention, the change in volume of the framework maylie in various ranges. The volume change is preferably approximately 10%of the longitudinal expansion of the embedded cells or cell groups.

For a pore size of 100 μm, individual cells, for example osteoblasts,are embedded in the framework. For a cell size of 10 μm, the dailyspatial extension distance is preferably at least 1 μm (lower limit),specifically, approximately 10% of the cell size.

For a pore size of 100-1000 μm according to the invention, mixed cellcolonies are preferably embedded in the pores, for example osteoblasts,fibroblasts, etc. A daily spatial extension distance of 10 to 100 μm isthen preferred, likewise approximately 10%, in this case of the colonysize.

For a pore size of 1000 μm-10 mm according to the invention, adherenttissue cells of connective tissue, callus, callus precursors, or othersare preferably embedded. The daily increase in spatial extension ispreferably 0.3-1 mm (upper limit), likewise approximately 10%, in thiscase of the tissue size.

According to the invention, the change in the extension distance is atleast 0.5 μm, particularly preferably at least 1 μm, more preferably atleast 10 μm, even more preferably at least 100 μm, very preferably atleast 1000 μm, very particularly preferably at least 10 mm, mostpreferably at least 100 mm.

According to the invention, the change in the extension distance ispreferably 100 mm maximum, particularly preferably 10 mm maximum, morepreferably 1000 μm maximum, even more preferably at least 100 μm, verypreferably 10 μm maximum, very particularly preferably 1 μm maximum,most preferably 0.5 μm maximum.

According to the invention, the rate of change of the volume is at leastgreat enough that cells adhering to the framework are distracted atleast 1 μm/day. According to the invention, the maximum rate of changeof the volume is great enough that cells adhering to the framework,i.e., osteogenic, callus-producing tissue, is distracted a maximum of 1mm/day. A more rapid distraction rate than 1 mm/day results indifferentiation of connective tissue instead of bone. As a result of thechange in volume, the framework transmits to the cells contained in theblood clot and adhered to the framework material, also in the interiorof the framework, biomechanical stimuli which trigger the body's ownregenerative forces, thereby forming new autologous bone material. Thisnew bone material does not differ from the original bone materialsurrounding the defect. The change in volume of the three-dimensionalframework results in biomechanical stimulus transmission throughout theentire space occupied by the framework, so that a biomechanical stimulusis transmitted to a much larger number of cells than for distractionosteogenesis from the prior art. According to the invention, thebiomechanical stimulus is preferably transmitted from the frameworkdirectly to osteoblasts.

For a distraction according to the invention, the biomechanical stimuliaccording to the invention are transmitted not only directly toosteoblasts adhering to the framework, but also indirectly viafibroblasts. According to the invention, fibroblasts adhering to theframework preferably further transmit the distraction stimulus toosteoblasts in a metered manner. Without being bound to theoreticalaspects, after completion of the distraction the fibroblasts in theso-called “null zone” also become osteoblasts and likewise form bone.For a decreasing distraction rate, the number of fibroblasts precedingthe osteoblasts changes.

In contrast, distraction osteogenesis from the prior art transmitsbiomechanical stimuli via a two-dimensional interface composed of boneor another material only to cells which directly contact thistwo-dimensional interface.

Thus, the invention provides a method in which a three-dimensionalframework is introduced into a bone defect, and the three-dimensionalframework in the bone defect changes in volume. As a result of thechange in volume, biomechanical stimuli are transmitted to cells, inparticular osteoblasts, present in the volume of the three-dimensionalframework, thereby stimulating the cells to form bone. Thethree-dimensional framework thus transmits biomechanical stimuli forutilization of the body's own regenerative forces.

The method according to the invention is therefore a three-dimensionaldistraction. In the context of the present invention, “three-dimensionaldistraction” is understood to mean distractive bone regeneration inwhich the biomechanical stimuli are transmitted to a bone fragment notonly at the interface, i.e., in two dimensions, but also throughout agiven volume, i.e., in three dimensions.

The method according to the invention uses the body's own healingmechanisms as a bioreactor. Thus, the bone formation occurs undernatural conditions, so that the necessary aspects such as growthfactors, hormones, and cell composition are implicitly taken intoaccount. In this manner the method according to the invention overcomesproblems which may arise as a result of the highly complex control forbone regeneration, as well as the problems of a slow and complicatedbone regeneration process using distraction methods from the prior art.

According to the invention, the bone defect is preferably revivifiedbefore introduction of the framework. According to the invention, in themethod according to the invention before introduction of the frameworkinto a bone defect this defect is preferably surgically revivified, andin particular bleeding is induced. A blood clot forms in the defect as aresult of the surgical revivification and the induced bleeding.

After the surgical revivification of the bone defect, according to theinvention a framework, in particular a framework according to theinvention, is preferably introduced into the bone defect. The frameworkmaterial of the introduced framework is enclosed, in particularcompletely enclosed, by the blood clot which forms; i.e., in particularthe interspaces, particularly preferably the pores, of the framework arefilled, particularly preferably completely, with the blood clot.

According to the invention, the framework preferably changes in volumeafter a defined point in time. According to the invention, the frameworkpreferably changes in volume after one day. According to the invention,the framework preferably changes in volume after one week. As a resultof the change in volume, according to the invention preferably also theshape and/or size of the interspaces, in particular pores, in theframework change, so that the framework simultaneously or successivelyemits in all directions, i.e., in three dimensions, stimuli to the cellsadhering to the framework which are distributed over the space. As aresult the blood clot does not shrink, but instead enlargescorresponding to the increase in volume of the framework. The cellsactivated by the framework may be converted to proliferating osteoblastswhich produce the extracellular matrix, and a callus may be formed whichsubsequently ossifies. When the framework according to the invention ispreferably biodegradable, the framework is subsequently absorbed and/ormetabolized. Thus, the bone defect may be filled with bone tissue whichaccording to the invention is preferably produced by the describedbiomechanical stimuli from the framework. According to the invention,artificially introduced bone replacement materials, growth factors, andother substances next to the framework may preferably be dispensed with.According to the invention, the newly formed bone material preferablydoes not differ, either histologically or in its biological or medicalvalue, from the original bone which surrounds it.

Since the framework according to the invention is preferablybiodegradable, the space resulting from the degradation of the frameworkmay be used for the extracellular matrix. According to the invention,the degradation of the framework may preferably be adjusted in such away that after a few weeks the framework degrades after it has emittedthe biomechanical stimuli, and the resulting space is occupied by theextracellular matrix.

According to the invention, within the scope of the method according tothe invention a framework is preferably used whose framework materialhas cell adhesive properties. The surface of the framework materialparticularly preferably has cell adhesive properties. The surface of theframework material in the framework plays an important role in thegrowth of cells from the blood clot. An adhesion of the cells to theframework material preferred according to the invention may beinfluenced by the surface chemistry, surface physics, and surfacetopography of the framework material. According to the invention thesurface of the framework material is preferably hydrophilic. For theingrowing cells, the interaction between the negatively charged cellmembrane and the electrical properties of the framework material surfaceis preferred according to the invention.

According to the invention, a biodegradable framework is preferablyintroduced into the defect region of a bone. According to the invention,the absorption of the framework material preferably begins 6 weeks afterthe framework is introduced into a defect region of a bone.

In another embodiment the invention relates to a further methodaccording to the invention for bone regeneration, in particular afurther three-dimensional distraction method, in particular anabove-referenced three-dimensional framework being introduced into adefect region of a bone and moved at that location. In this defectregion the framework is enclosed by a blood clot; i.e., the surfaces ofthe framework contact the autologous cells contained in the blood clot.According to the invention the interspaces enclosed by the frameworkmaterial are preferably filled at least partially, particularlypreferably for the most part, in particular completely, by the bloodclot. Since the framework has a three-dimensional structure, theframework surface is able to come into contact with the autologous cellscontained in the blood clot in the entire space that is filled by theframework. After the framework has been introduced into the defectregion of a bone the framework is moved within the bone defect. Themotion takes place in a controlled and directed manner, i.e., in apredefined direction at a defined rate. As a result of the motion, theframework transmits to the cells contained in the blood clot and adheredto the framework material biomechanical stimuli which trigger the body'sown regenerative forces, thus causing new autologous bone material to beformed. This new bone material does not differ from the original bonematerial surrounding the defect. The motion of the three-dimensionalframework results in biomechanical stimulus transmission throughout theentire space defined by the framework, so that a biomechanical stimulusis transmitted to a much larger number of cells than for distractionosteogenesis from the prior art.

Thus, the invention provides a method in which a three-dimensionalframework is introduced into a bone defect, and the three-dimensionalframework is moved in the bone defect. In this embodiment a change involume of the framework is not necessary, but is possible. As a resultof the motion, biomechanical stimuli are transmitted to cells, inparticular osteoblasts, which are present in the volume of thethree-dimensional framework, and the cells are thereby stimulated toform bone. The three-dimensional framework thus transmits biomechanicalstimuli for utilization of the body's own regenerative forces.

According to the invention, a method for regeneration of a bone ispreferred wherein at least one three-dimensional framework, comprising aframework material forming the framework fibers and interspaces enclosedby the framework fibers, is introduced into a defect region of a bone,the framework material being biocompatible and having a cell adhesiveproperty, and after introduction into the defect region the frameworkbeing moved in the bone defect in a predefined and controlled manner asa function of a force effect.

According to the invention, the framework is preferably moved at a rateof at least 1 μm/day and/or 1.5 mm per day maximum, particularlypreferably 1 mm per day maximum. According to the invention the motionis carried out continuously or discontinuously.

According to the invention, a biodegradable framework is preferablyintroduced into the defect region of a bone. According to the invention,the absorption preferably begins 6 weeks after the framework isintroduced into a defect region of a bone.

According to the invention, the three-dimensional framework used ispreferably a three-dimensional framework according to the invention.According to the invention, in the method the volume of thethree-dimensional framework preferably does not change during the motionof the framework.

According to the invention, the method according to the invention forstimulus transmission via a change in volume of a three-dimensionalframework may preferably be combined with the method according to theinvention for stimulus transmission via motion of a three-dimensionalframework. The disclosed preferred features of the method according tothe invention for stimulus transmission via a change in volume are inparticular also preferred features of the method according to theinvention for stimulus transmission via motion.

According to the invention, the motion of the three-dimensionalframework may preferably be carried out by means of at least oneexternally supplied force. According to the invention, the force ispreferably introduced using a tension cable or tension rod. According tothe invention the introduced force is preferably ultrasound. Accordingto the invention the force is preferably supplied by a magnet.

The invention further relates to the use of a biocompatible frameworkmaterial which is expandable and/or shrinkable in a predefined andcontrolled manner as a function of an internal or external force effect,and has a cell adhesive property for producing a three-dimensionalframework, comprising framework fibers made of the framework materialand interspaces enclosed by these framework fibers, for regeneration ofa bone, wherein the three-dimensional framework is or may be introducedinto a defect region of a bone.

Further advantageous embodiments of the invention result from thesubclaims. The invention is explained in greater detail below withreference to the following exemplary embodiment and the accompanyingfigures.

FIG. 1 shows a kit comprising three-dimensional frameworks in anapplicator in the form of a syringe; and

FIG. 2 schematically shows a three-dimensional framework which isintroduced into a bone defect, before and after a change in volume.

EXAMPLE

FIG. 1 shows a kit 100 which contains an applicator syringe 10 made ofsterilizable metal, on the open end 20 of which a disposable capsule 30,made of plastic, for example, is attached. The outwardly facing side ofthe disposable capsule 30 is provided with a protective cap 40. Thedisposable capsule 30 contains a plurality of three-dimensionalframeworks 50 in the form of a granulate. The three-dimensionalframeworks are injected via the syringe into a bone defect (notillustrated), for example in the jaw region.

The kit 100 according to the invention is used to inject the granulatecomposed of the three-dimensional frameworks 50 into a bone defect.After introduction into the bone defect, as a result of the structureand composition of the framework material according to the invention thevolume of the three-dimensional framework 50 changes, and forregeneration of the bone distracts the bone cells which in the meantimehave become embedded in the framework.

FIG. 2 a shows an absorbable framework 50, made of an elastic polymer,in a bone defect 200, specifically, immediately after this framework 50has been introduced into the bone defect 200, for example by use of akit 100. The framework 50 is composed of framework fibers 60 andinterspaces 70. Several osteogenic cells, for example osteoblasts 80,are already embedded in the interspaces 70 and adhere to the frameworkfibers 60. After being manufactured and before being introduced into thedefect 200, the framework 50 made of the elastic polymer has beenmechanically compressed, and then fixed in this compressed form byimmersion into a bath of a bioabsorbable crosslinking solution, forexample another polymer. After being introduced into the defect 200 thebioabsorbable crosslinking solution is continuously absorbed in apredefined manner, as the result of which, as schematically illustratedby the arrows in FIG. 2 a, the framework 50 spatially expands, i.e.,enlarges, in all three dimensions, so that, as shown in FIG. 2 b, aframework 50 with increased volume results as soon as the bioabsorbablecrosslinking solution has been completely absorbed. The increase involume results in distraction of the adhered cells 80 embedded in theframework 50.

1.-24. (canceled)
 25. A Three-dimensional framework for the regenerationof a bone, comprising framework fibers composed of at least oneframework material and interspaces enclosed by same, wherein theframework fibers have a thickness of 50 μm to 3000 μm, wherein theframework material is biocompatible, and expandable and/or shrinkable ina predefined and controlled manner as a function of a force effect andhaving a cell adhesive property, and wherein the framework has anelastic restoring force which allows a starting volume of the frameworkto be changed in a predefined and controlled manner as a function of theforce effect.
 26. The framework according to claim 25, wherein thestarting volume may be enlarged by filing the interspaces of theframework with a liquid, preferably a liquid containing biomoleculesand/or cells, particularly preferably blood.
 27. The framework accordingto claim 25, wherein the framework has a molded element, namely, acasing, interlacing, or adhesive, by means of which the framework is inan expanded or compressed starting volume, and wherein the startingvolume may be changed by removing the molded element, namely, thecasing, interlacing, or adhesive.
 28. The framework according to claim25, wherein the material of the molded element, namely, the casing,adhesive, and/or interlacing, is selected from the group comprisingfibrin, collagen, at least one polysaccharide, and mixtures thereof. 29.The framework according to claim 25, wherein the framework materialcontains a material selected from the group comprising polyglycolicacid, polylactic acid, poly(ε-caprolactone), poly(β-hydroxybutyrate),poly(p-dioxanone), a polyanhydride, and mixtures thereof.
 30. Theframework according to claim 25, wherein the framework material iscomposed of a material selected from the group comprising polyglycolicacid, polylactic acid, poly(ε-caprolactone), poly(β-hydroxybutyrate),poly(p-dioxanone), a polyanhydride, and mixtures thereof.
 31. Theframework according to claim 25, wherein the framework material iscomposed of polylactic acid and polyglycolic acid.
 32. The frameworkaccording to claim 25, wherein the framework material is anisotropic.33. The framework according to claim 25, wherein the framework materialcontains fibers of a fiber composite.
 34. The framework according toclaim 25, wherein the framework fibers of the framework material have athickness of 60 μm to 2000 μm.
 35. The framework according to claim 25,wherein the interspaces are designed as pores.
 36. The frameworkaccording to claim 25, wherein the interspaces have a diameter of 0.5 μmto 5 μm.
 37. The framework according to claim 25, wherein theinterspaces have a diameter of 5 μm to 25 μm.
 38. The frameworkaccording to claim 25, wherein the interspaces have a diameter of 100 μmto 1000 μm.
 39. The framework according to claim 25, wherein a portionof the interspaces have a diameter of 0.5 μm to 5 μm, a portion of theinterspaces have a diameter of 5 μm to 25 μm, and a portion of theinterspaces have a diameter of 100 μm to 1000 μm.
 40. The frameworkaccording to claim 25, wherein the framework material is biodegradable.41. A granulate composed of at least two frameworks according to claim25.
 42. A method for the regeneration of a bone comprising: introducingat least one three-dimensional framework having a framework materialforming framework fibers and having interspaces enclosed by theframework fibers into a defect region of a bone, wherein the frameworkfibers have a thickness of 50 μm to 3000 μm, wherein the frameworkmaterial is biocompatible, and is expandable and/or shrinkable in apredefined and controlled manner as a function of a force effect, andhas a cell adhesive property; and subjecting the framework is a forceeffect such that a starting volume of the framework changes in apredefined and controlled manner as a function of the force effect. 43.The method according to claim 42, wherein the framework is a frameworkaccording to claim
 25. 44. The method according to claim 42, comprisingrevivifying the bone defect before introduction of the framework.
 45. Amethod for the regeneration of a bone comprising: introducing at leastone three-dimensional framework having a framework material formingframework fibers and having interspaces enclosed by the framework fibersinto a defect region of a bone, wherein the framework fibers have athickness of 50 μm to 3000 μm, wherein the framework material isbiocompatible and has a cell adhesive property; and moving the frameworkin a predefined and controlled manner as a function of a force effectafter introduction into the defect region.
 46. Use of a biocompatibleframework material which is expandable and/or shrinkable in a predefinedand controlled manner as a function of an external force effect, and hasa cell adhesive property, for producing a three-dimensional frameworkcomprising framework fibers composed of the framework material andinterspaces enclosed by same, for the regeneration of a bone, whereinthe three-dimensional framework is introduced into a defect region of abone.
 47. Use of a three-dimensional framework according to claim 25 forproducing a bone regeneration kit.
 48. A method for producing athree-dimensional framework according to claim 25, wherein frameworkfibers composed of at least one nonbiogenic framework material areformed into a framework in an extrusion process, wherein the frameworkmaterial is biocompatible and is expandable and/or shrinkable in apredefined and controlled manner as a function of a force effect, andhas a cell adhesive property.